The trifluoromethyl group (CF.sub.3) is an important structural moiety in diverse classes of bioactive organic molecules. The CF.sub.3 group has a bigger van der Waals radius than that of a CH.sub.3 group and the same electronegativity as oxygen (Table 1).
The C--F bond in trifluoromethylated compounds results in added stability and lipophilicity of the molecule. As a consequence, the introduction of a trifluoromethyl group into organic molecules often changes their physical, chemical, and physiological properties. Compounds containing the trifluoromethyl group are found in a variety of commercially important dyes, polymers, pharmaceuticals, and agrochemicals. The dye industry has found that trifluoromethylated chromophores exhibit increased light fastness compared with the nonfluorinated compounds. Trifluoromethylated polymers have high thermal stability and enhanced mechanical and electrical properties. Many
TABLE 1 van der Waals radius and electronegativity of different groups Group/ van der Waals Group/ atom radius (.ANG.) atom Electronegativity CF.sub.3 2.7 CF.sub.3 3.5 CH.sub.3 2.0 CH.sub.3 2.3 CCl.sub.3 3.5 C 2.5 F 1.4 F 4.0 H 1.2 H 2.1 O 1.5 O 3.5 Cl 3.0
of these polyfluorinated polymers find application as liquid crystals. In a wide variety of agrichemicals and pharmaceuticals, the properties of the trifluoromethyl group, i.e., to increase lipophilicity and to act as an inhibitor of enzyme action, are key reasons for incorporation. Thus, a variety of reagents have been developed in order to introduce the CF.sub.3 group into organic molecules. Currently, there are three available methods for directly introducing a CF.sub.3 group into target compounds: (i) organometallic based on CF.sub.3 Cu, (ii) nucleophilic based on CF.sub.3 SiMe.sub.3, and (iii) electrophilic based on S-(trifluoromethyl)dibenzothiophenium triflate.
By nucleophilic and electrophilic are meant techniques or reagents that will transfer a CF.sub.3 group to an electron-deficient or electron-rich portion, respectively, of the target molecule. Organic molecules, while retaining electrical neutrality, will often show a partial separation of charge on their constituent atoms, especially due to the effect of electron-withdrawing or electron donating substituents. Aromatic rings and double and triple bonds are typical electron-rich environments. The presence of electron withdrawing substituents such as F.sup.-, Cl.sup.-, NO.sub.2.sup.-, N(SO.sub.2 CF.sub.3).sup.-, N(SO.sub.2 F).sub.2.sup.-, CN.sup.- can produce electron-deficient regions in molecules.
The introduction of a CF.sub.3 group into an electron rich environment is becoming more and more important in organic and bioorganic synthesis. It is not a trivial task, however. It is extremely difficult to generate the CF.sub.3 cation chemically, due to its high electronegativity (3.45). In 1984, Yagupol'skii reported two trifluoromethyl sulfonium salts, trifluormethyl-p-chlorophenyl(2,4-dimethylphenyl)sulfonium hexafluoroantimonate (1) and trifluoromethyl-p-chlorophenyl-p-anisylsulfonium hexafluoroantimonate (2), that were capable of acting as trifluoromethylating reagents. Yagupol'skii, L. M.; Kondratenko, N. Y.; Timofeeva, G. N. Zh. Org. Khim. 1984, 20, 115; Chem. Abstr. 1984, 100, 191494e. Compounds 1 and 2 react with sodium p-nitrothiophenolate in DMF to give p-nitrophenyl trifluoromethyl sulfide in high yield. However, 1 and 2 were synthesized from the extremely hygroscopic intermediate fluoro(trifluoromethyl)-p-chlorophenylsulfonium hexafluoroantimonate. Both products, 1 and 2, are also extremely hygroscopic. Furthermore, they are unreactive with the highly activated aromatic compound N,N-dimethylaniline.
In 1990, Umemoto reported power-variable electrophilic trifluoromethylating reagents (FIG. 1) that can transfer the CF.sub.3 group to different kinds of organic molecules. Umemoto, T.; Ishihara, S. Tetrahedron Lett. 1990, 31, 3579; Umemoto, T.; Ishihara, S. J. Am. Chem. Soc. 1993, 115, 2156. They react readily with strongly activated aromatic systems, e.g. N,N-dimethylaniline. Although these reagents are very useful, they are prepared by using multistep, inconvenient synthetic routes that require gaseous CF3I or CF3Br for the triflouromethylation reaction. These reagents, although available commercially, are expensive. ##STR2##
Umemoto also described several other trifluoromethylating reagents with varying power to transfer the CF.sub.3 group, which are shown in FIG. 2. The synthesis of these reagents was described as time consuming, and in some cases the yields were poor. Umemoto, T. Chem. Rev. 1996, 96, 1757-77. ##STR3##
There is an evident need for trifluoromethylating reagents which can be synthesized by straightforward, economical, efficient methods, and which are stable and easy to handle, and which will transfer the CF.sub.3 group in good yield to a wide variety of target molecules that have electron-rich centers.